QbD within the regulatory framework: Current and Future Perspectives provides an overview of Quality by Design (QbD), its regulatory framework, and perspectives on its current and future implementation. QbD is a science-based, risk-based, and proactive approach to pharmaceutical development and manufacturing. Key updates include the finalization of ICH Q8 Annex and ongoing QbD submission pilots. Critical steps for implementation involve defining target product profiles, critical quality attributes, and design spaces. Future perspectives include holistic versus unit operation approaches and integrating development and manufacturing teams. Business considerations center around benefits, requirements, costs, and flexibility within the evolving regulatory landscape.

1. QbD within the regulatory
framework: Current and Future
Perspectives
Asia Biomanufacturing Summit
Singapore
28 Oct 2009
Gary Khoo, PhD.
A-Bio Pharma

2. Outline
• QbD and regulatory background/ framework
• ICH Q8(R1) Update
• Current & future perspectives-
implementation and integration
• Business considerations
• Summary
2
Gary Khoo Asia Biomnaufacturing Summit 2009

3. QbD Framework:
Quality in Product Life Cycle
Product Process Scale-up & Commercial
Design Development Transfer Manufacturing
IND BLA
Clinical Phases
ICH Q8 (R) Pharmaceutical Development ICH Q11? Step 2 4Q 2009
PAT Guidance (2004)/ Process Validation Guidance (2008) draft
ICH Q9 Quality Risk Management
ICH Q10 Pharmaceutical Quality Systems
3
Adapted from Mukund Yelvigi, GMP International Workshop 2008, Mumbai Gary Khoo Asia Biomnaufacturing Summit 2009

4. QbD Framework:
What is Quality by Design?
• Science based, risk based, holistic and proactive
approach to pharmaceutical development
• Product, process understanding and process
control
4
Gary Khoo Asia Biomnaufacturing Summit 2009

5. QbD Framework:
Quality by Design: Design Space
Knowledge Space
Design Space
Control
Space
Acceptable Operating
Space
5
Ref: J Pharm Innov (2008) 3:60–68/ Bioprocess Intl. (2008) Mar 16-23 Gary Khoo Asia Biomnaufacturing Summit 2009

6. QbD Framework:
Why QdD? An FDA view point
• Hesitation to implement new, better technologies
• Little emphasis on manufacturing and its problems- high
wastage due to mistakes
• Development information empirical- inability to predict
scale-up/ roots cause of errors
• Differences in how products are regulated from region to
region
• Time consuming supplemental application for every
manufacturing change
• Dramatic increase in post-approval applications. Real
burden on FDA
• Less flexibility on the regulatory side
6
Gary Khoo Asia Biomnaufacturing Summit 2009

7. QbD Framework:
Changes in approach
Aspect Minimal Approach Enhanced QbD
Development Empirical, one variable at a time Mechanistic understanding,
multivariate understanding
Manufacturing Fixed; validation based on Adjust within design space;
Process initial full scale batches Lifecycle approach to
validation
Process controls In-process tests for go/no-go PAT tools for feed forward/
decisions feed back real time controls
Product Primary means of control Part of overall quality control
specifications strategy within design space
Control strategy Drug product quality controlled Real-time testing/ reduced
by testing (intermediate/ end end product testing
product)
Lifecycle Reactive (corrective action etc.) Preventive, continual
management improvement
7
Q8(R1) – Annex to Q8 Pharmaceutical Development, Gary Khoo Asia Biomnaufacturing Summit 2009

8. ICH Q8 Update:
Annex to Q8 Pharma (R1‐FDA/ R2 EMEA)
• 2 Part guide
– Part 1 was finalized (Step 4) in Nov 2005
– Part 2 only recently finalized (Nov 2008 –FDA/EMEA
Jun 2009)
• Part 1:Core document with baseline
expectations, optional information and regulatory
flexibility
– General principles of pharmaceutical development
– Introduce new concepts
• Part 2: Annexes act as a reference towards the
desired state and on the use if risk management
8
Robert Baum, PhRMA, Public ICH Meeting Brussels Nov 2008 Gary Khoo Asia Biomnaufacturing Summit 2009

9. ICH Q8 Update:
Updates on QbD submissions
• CMC/ Common Technical Document (CTD) sections S2
(Drug Substance) and P2 (Drug Product)
• July 2008, FDA OBP initiated pilot program for biologics.
– 10 supplements and 5 BLAs during initial phase.
• In Sep 2009, this deadline for pilot submissions
extended (increasing to 8 BLAs).
– INDs are also now included in the program.
• Mock P2 submission- Several organizations (e.g. EFPIA,
PDA) have done this with NCE.
• Latest PDA meeting (Frankfurt, 22-23 Sep 2009)
presented a Mock P2 based on an antibody process
9
FDA Federal Register: September 17, 2009 (Volume 74, Number 179) Page 47806-47807 Gary Khoo Asia Biomnaufacturing Summit 2009

10. ICH Q8 Update:
Q&A Release April 2009
• Establishing design space or using real time
release testing is not necessarily expected
• Design space:
– multivariate interactions not necessary if justified
– can be applicable to scale-up
– can be applicable to site-change
– can be developed over a single unit operation or a
series of unit operations
– Existing products are exempted but may be useful
• Control Strategy:
– systematic science and risk-based approach for
controls rather than narrow ranges
– control strategies exist even without a design space
10
June 2009 (EMEA/CHMP/ICH/265145/2009) Gary Khoo Asia Biomnaufacturing Summit 2009

11. Current/Future Perspectives:
Key steps for the implementation of QbD
Identify TPP
Identify CQA
11
A. Rathore and H Winkle; Nature Biotechnology vol 27, Jan 2009, 26-34 Gary Khoo Asia Biomnaufacturing Summit 2009

12. Current/Future Perspectives:
Critical Implementation strategy
• Target Product Profile: dosage, pK, half-life, safety profile,
sterility, immunogenicity
• Critical Quality Attributes: What protein attributes give rise
to target product profile.
• Defining product design space:
– Clinical design space
– Non-clinical studies and data
• Defining process design space
– Risk analysis, designed experiments, execution and analysis
– How are the CQAs created in the process?
• Refining product design space based on what is achievable
robustly (Scaled down models)
12
Gary Khoo Asia Biomnaufacturing Summit 2009

13. Current/Future Perspectives:
“Holistic” vs “unit operation” approach
• QbD for all unit operations necessary?
• Identify critical process steps based on efficacy
and purity (evidence based)
• Risk based approach
Upstream- Sa
fermentation/cell culture fe ty/
Pu
rity
Eff Capture
ica
cy/
Po
t en
cy
Polishing
13
Gary Khoo Asia Biomnaufacturing Summit 2009

14. Current/Future Perspectives:
Form An Integrated Team‐ Genentech Model
Biologics
Biologics Process Devt Commercial
Process
Process & Medium Scale scale production Fill & Finish
Research
Research production
2000lL – 20,000L
<10L
<10L 10L‐500L
• New cell line • Process development, • Process scale up • Vial filling, packing
development optimisation, scale‐up • DS Manufacturing facility • Lyophilization
• Expression • Productivity enhancement operations • Supply chain operations
engineering • QbD, PAT implementation • COGS improvement • COGS improvement
• Media design • Product quality & stability • Lean manufacturing • Lean manufacturing
• Novel product
FUNCTIONAL EXCELLENCE
ONE CMC TEAM
CELL CULTURE ANALYTICS PURIFICATION
•Analytical Biochemists •Chromatographers FORMULATION
•Molecular Biologists
•Biophysical Chemists •Protein Biochemists •Formulation chemists
•Microbiologists
•Protein Biochemists •Biochemical Engineers •Protein Biochemists
•Cell Biologists
•Engineers
•Virologists 14
Taken from Patrick Yang, Genentech, Inc., Nov. 5, 2007, APBioCheDSC, Taiwan. Gary Khoo Asia Biomnaufacturing Summit 2009

15. Current/Future Perspectives:
Global “Recipe”, Local control: Centocor Model
15
Taken from Paul McKenzie Bioproduction Forum Sep 2009 Gary Khoo Asia Biomnaufacturing Summit 2009

16. Business Considerations
• Enhanced process and product understanding
• Smoother transfers between R&D and
manufacturing
• Fewer manufacturing failures
• Broad spectrum of industry implementation
• CMC Post-Approval Change Management could
be a major factor for implementing QbD
• Will Q8, Q9, Q10 (Q11) remain optional or
become a regulatory expectation?
16
Robert Baum, Pharmaceutical Science and Clinical Pharmacology Advisory Committee
Gary Khoo Asia Biomnaufacturing Summit 2009
Meeting, Maryland, Aug 2009

17. Business considerations
• How will products made with the minimal approach fair
against “QbD” products (regulatory submissions/
“consumer perception”)?
• Different manufacturing expectations, control
procedures, etc.
– put new requirements on supply chain/quality
– Justification for greater resources to incorporate QbD
• Uncertainty over timing of and investment requirements
for QbD implementation
• How to manage QbD with Alliance Partners, CROs and
Suppliers?
• Design quality into manufacturing processes- how will
the management of each site be managed?
17
Robert Baum, Pharmaceutical Science and Clinical Pharmacology Advisory Committee
Gary Khoo Asia Biomnaufacturing Summit 2009
Meeting, Maryland, Aug 2009

18. Business Considerations:
Who can afford QbD?
Big
Pharma
model
Small
Biotech
model
18
Taken from Paul McKenzie Bioproduction Forum Sep 2009 Gary Khoo Asia Biomnaufacturing Summit 2009

19. Summary
• QbD has evolved, is still evolving with better
understanding of its implementation
• Have a macroscopic view about it’s
implementation and key requirements within
the regulatory framework
• QbD is still optional but it can benefit
business in long term
• QbD starts early; competent partners and
CMOs can make a difference
19
Gary Khoo Asia Biomnaufacturing Summit 2009